As of this writing, we are still without safe and effective therapeutic strategies for acute respiratory virus infections. Despite considerable efforts over the almost 50 years since its first description, supportive therapy alone remains the standard of care for the treatment of severe cases of respiratory syncytial virus (RSV), a disease with significant morbidity and mortality, particularly among infants born prematurely, and for which there is currently no vaccine. Even when a vaccine is available for a respiratory pathogen, such as for epidemic influenza virus, similar problems of disease prevention and management exist despite seasonal reformulation of vaccine preparations. While progress has been made toward the development of agents with antiviral activity in vitro, the clinical impact of these therapies has been disappointing. At the source of the problem is the observation that, once established, respiratory virus disease results from two concurrent pathologic components: ongoing virus replication and the resulting inflammatory response. Even when antivirals clearly inhibit virus replication, the biochemical and cellular inflammatory responses to the initial infection-related events continue despite diminished virus titer. Prolonged inflammation has been recognized as a significant component contributing to the pathologic sequelae of RSV and influenza virus, and most recently, to the morbidity and mortality of SARS-CoV infection. Our group has developed and characterized a mouse model of severe, acute respiratory infection using the highly virulent natural rodent pathogen, pneumonia virus of mice (PVM, family Paramyxoviridae, subfamily Pneumovirinae, strain J3666). Mice that are inoculated with fewer than 100 plaque forming units (pfu) develop acute lower airway disease characterized by progression to pneumonia, respiratory failure and death (see previous publications, since 2000). We have previously demonstrated that, analogous to influenza and RSV infection, the chemokine MIP-1?? is central to this virus-induced inflammatory process, and that interruption of MIP-1alpha signaling via the receptor CCR1 results in marked reduction in pulmonary inflammation (J Immunol, 2000). Furthermore, we have shown that the inflammatory events associated with pneumovirus infection are not inextricably linked to ongoing viral replication, as replication blockade with ribavirin does not mitigate the associated inflammatory events contributing to the infection-associated morbidity and mortality (J Virol, 2003; J Virol 2004). This year, together with my long-term collaborators at SUNY Upstate Medical University in Syracuse, we have published two original reports describing potential therapeutic advances made with this respiratory virus model system. In the first of these studies, we evaluated the clinical responses of pneumovirus-infected mice to combination therapy with the antiviral agent, ribavirin, and the CysLT1 cysteinyl leukotriene receptor antagonist, montelukast. We observed substantial virus replication in our mouse model of pneumovirus infection and significant accumulation of cysteinyl leukotrienes in lung tissue, the latter detected at levels that correlate directly with granulocyte recruitment to the airways. While administration of the nucleoside analog, ribavirin, reduced virus replication approximately 2,000-fold, the clinical outcomes as measured by morbidity and mortality, in response to ribavirin monotherapy were indistinguishable from those of the no-treatment controls. Similarly, montelukast therapy alone did not reduce granulocyte recruitment nor did it improve the clinical outcome. However, combined therapy with ribavirin and montelukast resulted in a significant reduction in morbidity and a substantial reduction in mortality (50% survival at t = 14 days and onward, compared to 10-20% survival in response to montelukast alone or to ribavirin alone, respectively, p < 0.01). These findings define further the independent contributions made by virus replication and by the ensuing inflammatory response to the detrimental sequelae of pneumovirus infection in vivo (Bonville et al., Antiviral Research, 2006). In the second original study, we explored relationships linking clinical symptoms, respiratory dysfunction, and local production of proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis. With a reduced inoculum of this natural rodent pathogen, we observe virus clearance by day 9, while clinical symptoms and respiratory dysfunction persist through days 14 and 17 postinoculation, respectively. Via microarray and ELISA, we identify expression profiles of proinflammatory mediators MIP-1alpha, MCP-1, and MIP-2 that correlate with persistent respiratory dysfunction. MIP-1alpha is localized in bronchial epithelium, which is also the major site of PVM replication. Interferon-gamma was detected in lung tissue, but at levels that do not correlate with respiratory dysfunction. Taken together, we present a modification of our pneumovirus infection model that results in improved survival and data that stand in support of a connection between local production of specific mediators and persistent respiratory dysfunction in the setting of acute viral bronchiolitis (Bonville et al., Virology, 2006). I have also co-authored an invited major book chapter entitled "Pneumonia Virus of Mice" currently in press in a volume entitled "Respiratory Syncytial Virus" in Perspectives in Medical Virology, vol. 12 (Cane P, ed).